This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To use live-attenuated SIV vaccines as a unique opportunity to study effective anti-immunodeficiency virus immune responses. We vaccinated 10 rhesus macaques with the live-attenuated SIV strain SIVmac239[unreadable]nef in 2006. We monitored the development of SIV-specific immune responses in this cohort using a variety of assays. The vaccinated animals, along with naive controls, were challenged with the uncloned "swarm" virus SIVsmE660 in 2007. Encouragingly, the cohort of vaccinated animals challenged with SIVsmE660 significantly controlled virus replication in comparison to naive controls for up to 4 months post-challenge. Of particular interest were animals expressing the MHC class I molecules Mamu-B*08 and [unreadable]B*17 which had near complete control of acute virus replication. The association of these two alleles with control of acute virus replication suggests that CD8+ T cells are the primary mediators of this protective immune response. At 11 months post-challenge four vaccinated animals were still controlling SIVsmE660 virus replication below 5,000 vRNA copies/ml plasma. To test our hypothesis that CD8+ cells are responsible for this low virus replication we administered an anti-CD8 antibody to deplete CD8+ cells from the peripheral blood in 2008. As anticipated we observed a recrudescence in virus replication in the absence of peripheral CD8+ cells. During this time we also wanted to determine whether the vaccine or challenge strains of the virus was replicating in the animals. We were surprised to find that only the vaccine strain of the virus was replicating in two of the four animals temporarily depleted of their peripheral CD8+ lymphocytes. Retrospective analysis throughout the course of the study confirmed that only the vaccine strain of the virus was detectable in these two animals at all time points tested, suggesting it is possible that they were able to achieve sterilizing immunity against a heterologous SIV challenge. Additionally, in the vaccinated animals losing control of virus replication during the chronic phase of infection we detected recombination between the vaccine and challenge strains of the virus. These recombination events may have contributed to the animals failing to contain virus replication. The research used and will continue to use WNPRC Immunogenetics &Virology Services.